It is known that stromelysin (human) has a wide substrate specificity spectrum, degrades many kinds of proteins including cancer cell matrix (IV-and IX-type collagens, laminin, proteroglycan, fibronectin, casein, elastin and gelatin) (J. Biol. Chem. Vol. 261, pp 14245-14255, 1986), and causes diseases such as rheumatoid arthritis (literature referred to above), metastasis of cancer cells (Proc. Natl. Acad. Sci., USA Vol. 83, pp 9413-9417, 1986), gingival inflammation (J. Periodont, et al. Res. Vol. 17, pp 183-190, 1982), glomerulonephritis (The Kidney, third ed. Vol. 1, pp 939-945, edited by Glassock, R. J., W. B. Sanders Co. Philadelphia), and the like, caused by a destruction of the outercellular matrix. Moreover, collagen has an important role in the destruction of the outercellular matrix (Arthritis Rheum., Vol. 27, pp 285-290, 1980), and stromelysin activates a precursor of collagenase (procollagenase), and indirectly, takes part in a control of collagenase activity (Biochem. J. Vol. 248, pp 265-268, 1987). Accordingly, to provide an inhibitor specific to stromelysin or collagenase is useful for treatment and prophylaxis of diseases in which these enzymes are involved, but to date, such an inhibitor having a low toxicity has not been developed.
Under the above circumstances, there is need for the development of a low molecular weight and low toxic inhibitor for stromelysin (human).
The present inventors, as a result of screening a wide range of microbial metabolites for a substance having an inhibitory activity to stromelysin (human), found that compounds represented by the general formula described hereinafter exhibit a remarkable stromelysin-inhibitory activity, and thus accomplished the present invention.